Placebo effects are treatment effects caused not by the biological action of the treatment, but by the meaning ascribed to it. Placebo treatments for a number of mental and physical disorders have been shown to have positive effects on health and well-being, making it important to understand the brain and psychological mechanisms through which these effects are produced. Recent fMRI evidence suggests that placebo-induced expectations of analgesia increase prefrontal cortex activity when pain is expected and decrease the brain's response to painful stimulation. The studies in this proposal examine placebo effects on brain and behavioral measures of pain, anxiety, and other negative affective responses using fMRI. Event- related fMRI designs are used to isolate brain responses to expectancy and painful stimulation, enabling an investigation of the interactions between preparatory and experiential processes. Two experiments examine the neural and neurochemical bases of the placebo response. One experiment compares the effects of placebo and an opiate analgesic drug on brain responses to painful stimulation, and tests whether the drug, like the placebo itself, works in part by activating positive expectancies. A second experiment compares brain placebo responses with and without an opioid antagonist drug, and tests whether blocking opioids eliminates placebo-induced activity in the brain. To examine the breadth of behavioral, psychological, and neural placebo effects, two experiments compare the mechanisms of placebo reductions in pain with placebo reductions in negative affect. A final experiment uses fMRI to compare the analgesic effects of placebo with analgesic effects of distraction, which tests the similarity in the neural mechanisms of these two effective pain-relieving techniques. Collectively, the studies examine how the brain mechanisms of analgesia relate to mechanisms for reducing negative affect more generally, providing potential insight into the reduction and management of negative affect in several mental health disorders, including anxiety disorders, depression, and Parkinson's (all of which benefit from placebo treatment). Further, the effectiveness of some pharmacological treatments for mental disorders has been shown to depend in part on interactions between drugs and expectancies. This proposal seeks to provide insight into the mechanisms of opioid-expectancy interactions at the psychological and brain systems levels of analysis.